1 - heterocyclic alkyl-1 2 3 4-tetrahydroquinazolinones and analgesic intermediates thereof

ABSTRACT

1-HETEROCYCLIC ALKY-,1,2,3,4-TETRAHYDROQUINAZOLINONES, ACID ADDITION SALTS THEREOF, AND INTERMEDIATE COMPOUNDS HAVING ANALGESIC PROPERTIES. A REPRESENTATIVE QUINAZOLINE COMPOUND IS 1-(2(1-PHENYL-4-PIPERAZINYL)ETHYL)-2-PHENYL-1,2,3,4-TETRAHYDRO-4 -QUINAZOLINONE. A REPRESENTATIVE ANALGESIC INTERMEDIATE IS 2(2-(4(1-PHENYL)PIPERAZINYL) ETHYLAMINO) BENZAMIDE.

United States Patent Oflice 3,635,976 1 HETEROCYCLICALKYL-1,2,3,4-TETRAHYDRO- QUINAZOLINONES AND' ANALGESIC INTER- MEDIATESTHEREOF Bola Vithal Shetty, Rochester, N.Y., assignor to PennwaltCorporation, East Orange, NJ. No Drawing. Filed Dec. 20, 1967, Ser. No.691,955 Int. Cl. C07d 51/48 US. Cl. 260-2564 19 Claims ABSTRACT OF THEDISCLOSURE l heterocyclic alkyl-l,2,3,4-tetrahydroquinazolinones, acidaddition salts thereof, and intermediate compounds having analgesicproperties. A representative quinazoline compound is 1- [2-(l-phenyl-4-piperazinyl) ethyl]-2-phenyl-l,2,3,4-tetrahydro-4-quinazolinone. A representative analgesicintermediate is 2[2-(4-[1-phenyl]piperazinyl) ethylamino] benzamide.

The invention relates to l-heterocyclic alkyl-1,2,33,4-tetrahydroquinazolinones, acid addition salts, and intermediatecompounds thereof characterized by having analgesic properties.

More particularly the invention relates to compounds from the groupconsisting of A, compounds of the formula:

Where X is NH, NR CH CHR O or S, R is OH or OCOR where R, is loweralkyl,

e.g., CH3, CH CH CH 01 3,635,976 Patented Jan. 18, 1972 R and R, can bejoined together to form with the two position carbon atom to which theyare attached, a cycloaliphatic or heterocyclic ring substituted orunsubstituted preferably having 3 to 10 carbon atoms,

R is H, loweralkyl, aryl, substituted aryl, or aralkyl;

B, compounds of the formula:

where X is NH, NR CH CHR where R is OH or OCOR and R is loweralkyl, or

O or S,

R is H, loweralkyl, hydroxy, loweralkoxy, halogen, amino, or substitutedamino group (e.g. NHCHO, NH-CH A is (CH where n is 1-5, or a branchedalkyl with 3 to 5 carbon atoms,

R is H, loweralkyl, aryl, substituted aryl (e.g. OH, 0CH NH CH Cl),aralkyl, or substituted aralkyl (e.g. OI-I, OCH NH CH Cl),

R is H, loweralkyl,

R is H, loweralkyl, acyl, benzoyl, aryl, substituted aryl, aralkyl,substituted aralkyl, benzyl, substituted benzyl (e.g. OH, OCH NH CH C1),or heterocyclic,

R7 is OH, loweralkoxy, (e.g. 0CH OCH -CH heterocyclic (e.g.

NH NH-- loweralkyl, or --N=(disubstituted with loweralkyl) and Cpharmacologically acceptable acid addition salts of the above compoundsof A and B.

The compounds of the present invention may be prepared by variousmethods which are known in principal. A convenient method is illustratedin the following diagram of a general synthetic route, wherein R, R andR represent radicals such as shown in the formulae above. There are alsogiven below two synthetic schemes for the preparation of specificcompounds of this invention. The schematic and short handrepresentations are those known in the art.

GENERAL SYNTHETIC ROUTE N-CH2-CHC1 i ing R R m H B C d m H 2 t RIC H m Hw I. N C M W m Wm A d mmme m C I a n R R M R n H m c N m \H R N C OSynthetic scheme for the preparation of2-[2-(4-[1-phenyl]piperazinyl)ethylamino1-benzamide 1-[2-(1-pheny1- 4piperazinyl)ethyl] 2-phenyl-1,2,3,4-tetrahydro-4- quinazolinone lHCl Q-N-CHzCH OH H01 S0011 :H20H2N CHO Alternate route for the synthesis of1-[2-(1-phenyl-4-piperazinyl) ethyl]2-pheny1-l,2,3,4-tetrahydro-4-quinazolinone \COR1 R H, OH, lower alkoxy,lower alkyl, halogen, R, R R R R R A=same as given in the generalstructural formula first above written.

formed into their acid addition salts, or quaternary ammonium salts bycustomary methods. For instance the acid addition salts may be obtainedby dissolving the free base in a suitable solvent and acidifying thesolution with the desired acid. Suitable pharmacologically effectiveacid addition salts include the sulfates, hydrochlorides, phosphates,cyclohexyl sulfamates, maleates, citrates, tartrates, succinates, ethanedisulfonates, methane, sulfonate, isethionates, and the resinatesobtained by reacting the amine group of the compound with a cationexchange resin such as a sulfonic, carboxylic, or phosphoric acid cationexchange resin.

To prepare a quaternary ammonium salt the free base is merely reactedwith a suitable quaternizing agent, such as an alkyl halide, an aralkylhalide or dialkyl sulfate, preferably in the presence of an inertorganic acid.

The following working examples further illustrate the invention.

EXAMPLE I Preparation of 2-[2-(4-[l-phenyl]piperazinyl)ethylamino]-benzamide 1-phenyl-4- 2-hydroxyethyl piperazine Step 1:

N-phenylpiperazine: 5 l 9 gms. Ethylene oxide: 179 gms. Methanol(absolute): 800 ml.

Charged phenylpiperazine and methanol, cooled to 0 to -10 and added theethylene oxide over 1% hours. (Rate of addition is not important.)Removed cooling bath and allowed temperature to rise to 40, cooling tokeep below 40 until temperature stops rising. Heated at 65 for 1%. hoursand added the methanol solution to hot heptane (gradually). Methanol wasazeotroped out, adding heptane to keep the volume at 10 liters. Decantedfrom the insoluble oil and cooled to room temperature to give 336 gms.,M.P. 79-80.5, plus a hard mass which apparently resulted from initialoiling out and then crystallization of the oil. This was extracted withhot heptane to give another 119 gms. of product. Yield:69%.

1-phenyl-4-(2-hydroxyethyl)piperazine hydrochloride Step 2:

1-phenyl-4-(Z-hydroxyethyl)piperazine: 335 gm. Methanol (anhydrous):1075 ml.

HCl gas was bubbled into a solution of the 1-phenyl-4- (2-hydroxyethyl)piperazine in methanol until the mixture was acidic, cooling to keep thetemperature below 30. The solid was filtered, washed with methanol andair dried to give 202 gms., M.P. l5l153. The mother liquor was used todissolve 119 gms. of 1-phenyl-4-(2-hydroxyethyl)piperazine and thesolution acidified as above to give 179 gms., M.P. 153183. Concentrationof the mother liquor gave 116 gms., crop 2, M.P. 150-152. Yield=92.7%.

1-phenyl-4-(2-chloroethyl)piperazine dihydrochloride Step 3:

1 phenyl 4 (2 hydroxyethyDpiperazine HCl:

200 gms. chloroform: 1450 ml. Thionyl chloride: 110 ml.

The HCl salt was suspended in chloroform and thionyl chloride added over1% hours. The reatcion mixture was refluxed 6 hours, cooled to roomtemperature, filtered and washed solid with chloroform. The air driedproduct was recrystallized from 2.5 liters methanol to give 214 gms.,M.P. 215-218. Yield=87%.

2-[2-(4-[1-phenyl] piperazinyl)ethylamino]benzamide Step 4:

o-Aminobenzamide: 3260 gms. 1 phenyl 4 (2-chloroethyl)piperazinedihydrochloride: 6500 gms. Triethylamine: 7070 gms. Diglyme: 751.

The reaction was run in 10 portions. The above materials were heated at150 for 24 hours, cooled to room temperature and the solid filtered andwashed with diglyme. The filtrate was evaporated to dryness on therotovap at about 70 C. The diglyme residue was stirred with 2 l.isopropanol and the solid filtered and washed with isopropanol, thenwith ether. Combined solids were recrystallized from 40 l. of about EtOH20'% water to give 1561 gm., M.P. 161.52.5. Concentration of thefiltrate to 10 1. gave a 2nd crop of 587 gms. which was recrystallizedto give 477 gms., M.P. 161.52.5.

EXAMPLE II Preparation of 1-[2-(1-phenyl-4-piperazinyl)ethyl]-2-phenyl-1,2, 3,4-tetrahydro-4-quinazolinone Step 1:

2 [2 (4 [1-phenyl]piperazinyl)ethylamino]benzamide: 1000 gms.Benzaldehyde: 342 gms. Piperidine: 148 gms. Ethanol: 9 1.

Charged all starting materials and refluxed 24 hours. The reaction wasrun in 2 parts and the reaction mixtures combined, seeded and cooled toroom temperature overnight. The solid was filtered and washed to give960 gms. crude. The crude product was recrystallized from 7.2 l. benzeneand the product was dried at l20 and 2 mm. pressure for 10 hours to give550 gm., M.P. 142.53.5. Concentration of the benzene mother liquor gavea 2nd crop of 235 gm. (before drying under vacuum).

31 EXAMPLE III Preparation of l-[2-(1-phenyl-4-piperazinyl)-ethyl]-2-phenyl-4[1H]-quinazolinone hydrochloride To a solution of 16.2 gm.(0.05 M) of the substituted benzamide (III, prepared as in Example I,Step 4) in 200 ml. of pyridine, 7.73 ml. (0.55 M) of benzoyl chloridewas added dropwise at 15 The solution was refluxed for 2 hours andcooled to room temperature, and the solid formed was filtered off. Itwas recrystallized from 275 ml. of hot water to yield gm. (44%) of whitesolid melting at 260-262 C.

Preparation of 1-[2-(1-phenyl-4-piperazinyl)-ethyl]-2-phenyl-1,2,3,4-tetrahydro-4-quinazolinone The free base of the abovematerial was liberated, and 2.5 gm. (0.0061 M) of this and 0.3 gm.(0.0022 M) of aluminum chloride were put into 120 ml. of diglyme. Tothis was added 0.29 gm. (0.0076 M) of sodium borohydride in 30 ml. ofdiglyme, dropwise over minutes at room temperature.

The temperature was brought to 85 and kept there for 1 hour, and thenthe solution was cooled to in an ice bath and 20 ml. of water was addedalong with enough hydrochloric acid to bring the pH to 5.

The clear solution was taken down on the rotovap to give a yellow solid,which was triturated with cold water and filtered to give 3.2 gm. ofwhite solid, melting at 268270 (decomp.).

1.0 gm. of the solid was freed from its salt form and recrystallizedfrom 10 ml. of benzene to yield, after drying overnight at 95, 0.25 gm.of white solid, melting at 142143 C. A mixed melting point With anauthentic sample of 740-222 showed no depression.

EXAMPLE IV Preparation of 2-[2-(4-[ l-phenyl]piperazinyl)ethylamino]benzamide cyclohexyl sulfamate 2 [2 (4 [1phenyl]piperazinyl)ethylamino]benzamide: 15.2 gms.

Cyclohexylsulfamic acid: 9.0 gms.

Tetrahydrofuran: 300 ml.

The benzamide was dissolved in about 250 ml. tetrahydrofuran and asolution of cyclohexylsulfamic acid in about 50 ml. tetrahydrofuran wasadded. The solid which precipitated was filtered, washed, and dried andthen recrystallized from a mixture of 600 ml. isopropanol, 100 m1.methanol, and 10 drops of 10% NaOH to give 13 gms., M.P. 152-4.

EXAMPLE V Preparation of 2-[2-(4-[1-phenyl]piperazinyl)ethylamino1benzamide phosphate 2 [2 (4 [1 phenyl] piperazinyl)ethylaminoJbenzamide: 90 gms.

Phosphoric acid (85%): 45 ml.

Ethanol (95% )1 450 ml.

The benzamide Was suspended in ethanol and a mixture of 45 ml.phosphoric acid in 225 ml. water was added. The mixture was stirred,heated to solution, filtered, and left overnight. The solid product wasfiltered, washed with ethanol, dried, and recrystallized from 450 ml.ethanol and 240 ml. water to give 64 gms., MAP. 1856.5

EXAMPLE VI Preparation of 2-[2-(4-[1-phenyl-piperazinyl)ethylaminoJbenzamide hydrochloride 2 [2 (4[1 phenyl1piperazinyl)ethylamino]benzamide: 250 gms.

Ethanol 95%: 41.

HCl concentrated: 71 ml.

32 A solution of 71 ml. concentrated HCl in 213 ml. water was added to ahot solution of the benzamide in 4 l. of ethanol. The mixture was cooledto 30 and the solid filtered, washed with alcohol, and dried over P 0under vacuum to give 249 gms., M.P. 257.5-60 (dec.).

EXAMPLE VII Preparation of 2-[2-(l-[p-methoxyphenyl]-4-piperazinyl)ethylaminoJbenzamide lp-methoxyphenyl) -4- 2-hydroxyethyl piperazinehydrochloride Step 1:

1-(p-methoxyphenyl)piperazine: 26.5 gms. Methanol (absolute): 100 ml.Ethylene oxide: 7.35 gms.

1- (p-methoxyphenyl -4- 2-chloroethyl piperazine dihydrochloride Step 2:

1 (p-methoxy-phenyl)-4-(2-hydroxyethyl)piperazine hydrochloride: 30 gms.Chloroform: 500 ml. Thionyl chloride: 33 gms.

The HCl salt was suspended in chloroform and thionyl chloride addeddropwise, at room temperature, over 1 hour. The reaction mixture wasrefluxed 8 hours, stirred 12 hours at room temperature. The solid wasfiltered and recrystallized from 180 ml. MeOH and 40 ml. ether to give24.5 gms., M.P. 220-8.

2- 2-( 1- [p-methoxyphenyl] -4-piperazinyl) ethylamino] benzamide Step3:

1 (p methoxyphenyl)-4-(2-chloroethyl)piperazine dihydrochloride: 24 gms.o-Aminobenzamide: 10 gms. Triethylamine: 30.7 ml. Diglyme: 250 ml.

All starting materials were combined and heated at 150 for 96 hours. Thereaction mixture was cooled, filtered, and the filtrate concentrated onthe rotovap. The residue was triturated with 200 ml. isopropanol,filtered, and the solid recrystallized from 300 ml. ethanol and thenfrom a mixture of 60 ml. dimethylformamide and 100 ml. water to give 7.8gms., M.P. 1702.

EXAMPLE VIII Preparation of l [2 (1-phenyl-4-piperazinyl)ethyl]-2-phenyl 1,2,3,4 tetrahydro 4 quinazolinone hydrochloride 1 [2 (1phenyl-4-piperaziny1)ethyl]-2-phenyl-l,2,3,4-

tetrahydro-4-quinazolinone: 10 gms. Ethanol ml.

The base was dissolved in ethanol and 10 ml. of 2.5 N HCl was added.After several hours the solid was filtered, washed with ethanol, anddried over P 0 to give 100% yield of the HCl salt, M.P. 26771 (dec.).

33 EXAMPLE IX Preparation of 1 [2 (l-phenyl-4-piperazinyl)ethyl] -2-methyl 1,2,3,4 tetrahydro 4 quinazolinone hydrochloride 2 [2(4-[1-phenyl] piperazinyl)ethylamino]benzamide:

32.4 gms.

Acetic acid, glacial: 200 ml.

l,1dimethoxyethane: 12.2 ml.

The benzamide was dissolved in acetic acid, dimethoxyethane added and3.5 ml. concentrated sulfuric acid added dropwise. The reaction mixturewas stirred 5 hours, left overnight at room temperature, concentrated onthe rotovap, and 75 ml. water added to the residue. The solution wasmade alkaline with 10% NaOH and extracted with benzene. The benzeneextract was washed with water, dried, and concentrated to dryness. Thebenzene residue was dissolved in 90 ml. benzene and 100 ml. hexane wasadded to give 32 gms. crystalline material. This was suspended in 50 ml.95% ethanol, 25 ml. 2.5 N HCl added and heated to solution. A few moreml. 2.5 N HCl was added, the solution treated with charcoal and cooledto give 30.5 gms. of the HCl salt. This was recrystallized twice from a84% ethanol-16% water mixture to give 18.5 gms., M.P. 242-8 (2.05% waterof hydration).

EXAMPLE X Preparation of 1' [2-(1-phenyl-4-piperazinyl)ethyl]-1-methylspiro [piperidine 4,2'(l'H) quinazolin]-4'- (3'H)-one sulfate 2 [2(4-[l-phenyl]piperazinyl)ethylamino]benzamide:

19.4 gms.

Acetic acid, glacial: 120 ml.

l-methyl-4-piperidone: 12 ml.

The benzamide was dissolved in acetic acid, 1-methyl-4- piperidone addedand then 1.3 ml. sulfuric acid added dropwise. The reaction mixture wasstirred 3 hours at room temperature, left over the weekend at roomtemperature, and heated 5 hours at 90.

l-methyl-4-piperidone (2 ml.) was added, the reaction mixture heated 7hours at 90, left overnight at room temperature and concentrated on therotovap. The residue was dissolved in 150 ml. water. After several hoursthe solid was filtered off. The crude product was recrystallized twicefrom water and dried over P to give 11 gms. product, M.P. indefinite(starts at 160), which contained 5% water of crystallization.

PHARMACOLOGICAL ACTIVITY OF COMPOUNDS OF THIS INVENTION The compounds ofthis invention, when administered to several species of experimentalanimals by various routes, have been found to possess effectiveanalgesic activity and can antagonize strong narcoticanalgesics asindicated by use of conventional testing methods. These compounds arecharacterized further by a very low order of toxicity in experimentalanimals and appear to be substantially non-addicting. In addition to theprimary analgesic activity these compounds possess other pharmacologicaleffects of potential utility at higher dose levels than those requiredfor analgesia, but within an adequate margin of safety for considerationof therapeutic application. Among these other pharmacological propertiesare tranquilizing activity, hypothermic activity, anticonvulsantactivity, and antihistaminic activity.

Suspensions of compound 740-222 (the compound of Example II) as thebase, and solutions and suspensions of the hydrochloride salt of 730-372(the compound of Example I) have been used in testing for analgesia andother pharmacological properties. A 2% suspension of soluble starch(Clearjel) in distilled water was employed as a vehicle for thecompounds and the solutions of 730- 372 were prepared in distilledwater. Different lots of the 34 compounds prepared as disclosed have notbeen found to display significant differences.

Established methods were employed for demonstrating analgesia andconsisted of the following: A modification of the Eddy and Leimbach(Exp. Biol. & Med. :729 (1957)) mouse hot plate test was used. The endpoint of this test is the time required for animals, pretreated withvarious dose levels of the test compounds or standard analgesics such asmorphine or codeine, to react to the heat stimulus by raising or lickingthe feet or by jumping. The dose of compound or standard which resultsin significant analgesic effect in 50% of the animals is calculated onthe basis of the number showing response times exceeding the meancontrol time by two seconds or more. Ten animals are used for each doselevel.

In addition to the hot plate method, the writhing test described bySigmund et al., Soc. Exp. Biol. and Med. 95 :729 (1957) has been appliedin both rats and mice as further indication of analgesics. This methodhas been reported to be of value in detecting activity of narcoticantagonist analgesics which sometimes do not exhibit activity with useof other conventional methods. The stimulus of intraperitoneal injectionof phenylbenzoquinone results in a writhing syndrone characterized byperiodic twisting and stretching of the body with extension of the hindlegs. Frequently of writhing has been shown to be reduced or preventedby prior administration of narcotic and non narcotic analgesics. A testcompound is considered to have analgesic properties if, by prioradministration, it is able to reduce significantly the number of Writhesfrom that obtained by a group receiving vehicle alone. The dose ofcompound protecting 50% of the animals is determined and expressed asthe ED Ten animals are used at each dose level.

Certain compounds have the ability to antogonize the activity of strongnarcotic analgesics in animals, whereas when tested by conventionalmethods in mice and rats little or no analgesia can be demonstrated.Some of these compounds have been shown to be very effective analgesicsin man. The compounds of this invention were tested for their ability toantagonize narcotic analgesics by two different tests. When oxymorphone,a morphine derivative, is administered to mice, pupil dilation occurs.It has been demonstrated in our laboratory that narcotic antagonists areable to reduce this mydriatic response significantly if administeredprior to oxymorphone whereas narcotic agents such as morphine andcodeine cause no change or an increase in the pupil size. Another testused for narcotic antagonist activity was published by Harris & Pearson.This test is modification of the DAmour & Smith method.

In the original method the time required for rats to flick their tailsfollowing application of a heat stimulus is taken as a measure ofanalgesic potency. As modified by Harris & Pearson the drug being testedfor narcotic antagonism is administered prior to the morphine. Anantagonist reduces or prevents analgesia from the morphine. Both of themethods described have been utilized to test the narcotic antagonistcharacteristics of the compounds of the examples.

Analgesic activity Results: Table I summarizes the results obtained'with the compounds of this invention when tested for analgesic activityand provides a comparison with morphine and codeine.

Compound 740222 (the compound of Example II) is more active by the oralthan the parenteral route, an unusual characteristic. Analgesic activityof this compound is of the same order as codeine and slightly less thanmorphine by the oral route utilizing the hot plate test in mice. By thewrithing test in mice this compound has approximately one-third theactivity of morphine and is about 1 /2 times as active as codeine. Thewrithing syndrome is also 50% blocked in rats pretreated with 10 mg./kg.of 740222 by the oral route. The compound produces a slight antagonismof oxymorphone induced mydriasis in mice by the intraperitoneal routeonly. It was not effective by the subcutaneous route in antagonizingmorphine analgesia in rats. This may have been due to its lowsolubility, causing a poor absorption by this route.

The acute toxicity of compound 740222 by all routes tested in mice isgreater than 1 gm./kg. body weight which is substantially aboveeffective analgesic doses. The therapeutic index i.e. the relationshipof the lethal dose to the effective dose for this compound by the oralroute is greater than 300. The highest dose that can be administeredwithout gross evidence of sedation is approximately 10 times thatnecessary to produce effective analgesia.

Table I also indicates the results of testing compound 730-372 (thecompound of Example I) for analgesic activity. This compound is moreactive by the parenteral routes than by the oral route. By the hot plateand writh ing tests 730-372 has been found to be approximatelyequivalent to or slightly more active than morphine. It was effective inantogonizing oxymorphone induced mydriasis and at lower dose levelsantagonism of morphine analgesia was observed in rats. These datasupport the contention that this compound is a narcotic antagonistanalgesic.

The acute toxicity of compound 730-372 (as indicated by the LD is shownin Table II to be greater than 800 to 1000 mg./kg. body weight whenassessed in mice by various routes of administration. The therapeuticindex is greater than 300.

Tranquilizer activity A tranquil sedation has been observed in mice,rats, cats, and monkeys following administration of these compounds indoses exceeding those that are required for analgesia. In additionfurther indirect evidence for tranquilizer activity has been obtained byapplication of a method described by Witkin et al., J. Pharmacol. andExp. Ther. 126:330 (1959).

This test is based upon observations that the pinna reflex of the mouseis blocked at relatively low doses of major tranquilizer drugs whereasvery high doses are needed to block the corneal reflex. A ratio of EDcorneal/ED pinna exceeding unity is taken as evidence of tranquilizertype action. The compound 740222 (the compound of Example II) displayeda ratio of greater than and is therefore classified as possessingtranquilizer activity. Preliminary results with compound 730-372 36 (thecompound of Example 1) indicate a ratio of approximately 0.5 which iswithin the range of ratios expected with sedatives (0.3 to 0.7) andapproaches the range of ratios for minor tranquilizers with centralmuscle relaxant activity.

These compounds have been tested for antihistaminic properties utilizingsegments of isolated guinea pig ileum suspended in Kreb Ringer solutionmaintained at 37 C. with aeration of a O +5% CO mixture. Contrac tionswere elicited by histamine phosphate. The concentration of compoundrequired to block these contractions when added to the tissue bath priorto introduction of histamine is taken as evidence for antihistaminicaction. Table III reveals that 740-222 has about the same activity asthe standard antihistaminic diphenhydramine and compound 730-372 isabout half as active as the standard.

Hypothermic effect Rectal temperatures were recorded periodically inmice following administration of 740222 by oral route. Codeine was usedfor comparison. FIG. 1 indicates that this compound effectively reducedbody temperature in normal mice. Compound 730-372 was also effective inthis respect.

Anticonvulsant activity Administration of pentylenetetrazel (Metrazol)to mice.

resulted in convulsive seizures which could be blocked or reducedeffectively by anticonvulsant agents, such as phenobarbital. Compound740222 administered by the oral route was able to antagonize theseMetrazol induced convulsions in mice. Compound 730-372 was not effectiveby the subcutaneous route in this respect.

Gastrointestinal motility suppression The opium alkaloids are the mosteffective agents for causing constipation or treating diarrhea. It hasbeen found that 720-222 is effective in suppressing intestinal motilityin mice. The method used was a modification of that described by Britain& Collier (J. Physiol. 141:14p 195 8)). In this method the length ofintestine traversed by an orally administered suspension of charcoal ismeasured. Compounds which inhibit motility effectively, reduce thepercentage of the small intestine traversed. 740- 222 reduces gutmotility as indicated by a comparison with codeine. This effect is lessimportant with compound 730-372.

TABLE I.-ANALGESIC ACTIVITY OF 740222 AND 730-372 HNSD/EDsu LDsol m Hotplate writhing Compound Species Route EDao EDm H.P. writhing H.P.writhing Rat; s.c. 2 5 DAmonr Smith Rat Tail Flick sub. cut. EDsa 18mg./kg.

Morphine Mouse p.o. 3 4.0 10.0 570 267 do i.p. 2.5 4.0 Rat Tail Flicksub. cut. ED50 15 mgJkg.

Codeine Mouse p.o. 20 17 5.0 5.9 27 32 .do i.p. 12 2.6 8.7

No'rE.-HNSD =highcst dose which can be administered without developmentof any gross symptoms such as depression,

convulsions, etct Preliminary result.

NOTn.Compounds were administered in 2% Clearjel as a suspension exceptin the case of i.v. 730-372A which was a solution (5 mg./ml.) indistilled water. Exact LDso values could not be obtained due to lowcompound solubility limiting the concentration which could beadministered. Toxici-ties have only been run with male animals to date.Studies using females will begin shortly.

TABLE III.ACTIVITY OF 740-222 AND 730-372 ON ISOLATED GUINEA PIG ILEUMSCREEN Amount in micrograms to produce a 50% block of AcetylcholineHistamine Compound:

740-222 1, 000 0. 5 730-372 126 0. 8 Diphenhydramine 6 0. 4

What is claimed is: 1. A compound selected from the class of compoundsconsisting of A, compounds of the formula:

R is H, loweralkyl, hydroxy, loweral-koxy or halogen,

A is (CH where n is 1-5, or a branched chain alkyl with 3 to 5 carbonatoms,

R is H, loweralkyl, phenyl, or phenyl substituted in the ring with NHOH, OCH or Cl,

R is H, loweralkyl,

R and R each is H, phenyl, or phenyl substituted in the ring with NH OH,OCH or Cl, phenylalkyl or phenylalkyl substituted in the ring with OH,NH OCH CH or C1, or loweralkyl,

R and R; can be joined together to form with the 2-position carbon atomto which they are attached, a methylene ring having 3 to 10 carbonatoms,

R is H, loweralkyl, phenyl or phenylalkyl substituted as for R and R andB pharmacologically acceptable acid addition salts of the abovecompounds.

2. The compound A of claim 1.

3. The compound B of claim 1.

4. The compound A of claim 1 wherein R is H, A is R is phenyl, R is H, Ris H, and R is phenyl, R is H, and X is NR 5. The compound A of claim 1wherein A is CHCHz- 38 X is NR R is phenyl, R R R are all H, R, isphenyl and R is 6-OCH 6. The compound A of claim 1 wherein A is CH CH or-CHCH2 H3 X is N-R R is phenyl, R R R are all H, R, is phenyl and R is6-OH.

7. The compound B of claim 1 wherein A is -CH2-CH2' OI -CHCH2 in. X isNR R is phenyl, R is H, R is H, R; is NHg, and R is 5-OCH 8. Thecompound B of claim 1 wherein A is CH CH or -CH-CH2 CH3 X is NR R isphenyl, R is H, R is H, R is NH and R is 5-OH.

9. The compound A of claim 1 wherein A is -CHCH2 CH X is NR R isp-hydroxyphenyl, R, R R and R are all H, and R is phenyl.

10. The compound A of claim 1 wherein A is CH CH or CHCH (1H, X is NR Ris p-methoxyphenyl, R, R R and R are all H, and R is phenyl.

11. The compound A of claim 1 wherein A is CH CH or H; X is NR R iso-tolyl, R, R R and R are all H and R is phenyl.

12. The compound A of claim 1 wherein A is "-CH2CH2' 0r CHCH2-- a X isNR R is phenyl, R R and R are all H, R; is phenyl, and R is 7-NH 13. Thecompound A of claim 1 wherein A is CH2CH2 Or CHCH2 a X is NR R isphenyl, R R and R are all H, R, is phenyl, and R is 6-NH 14. Thecompound A of claim 1 wherein A is -'-CH2CH2-- 0r CHCHza X is NR R isphenyl, R, R R and R are all H, and R is p-aminophenyl.

15. The compound A of claim 1 wherein A is |CHCH2 CH3 X is NR R isphenyl, R, R R and R are all H, and R is benzyl.

16. The compound A of claim 1 wherein A is CH2CH2 OI CHCH2 39 40 X is NRR is phenyl, and R, R R R and R are 19. The compound of claim 14 whereinAis CH CH all H. and X is N-phenyl.

17. The compound A of claim 1 wherein A is -CH CH or References CitedCI-IOH: 5 UNITED STATES PATENTS (3H 3,497,514 2/1970 Okumura et a1.260-256.4 Q

X. is NR1, R1 is phenyl, R, R2, and R5 are all H, and R3 and R togetherare CH CH CH CH ALEX MAZEL Pnmry Exammer 18. The compound A of claim 1wherein A is 10 R. J. GALLAGHER, Assistant Examiner X is NR1, R isphenyl, R, R2, R3, R are all H, and R 15 251 is CH3

